GB2194234A

GB2194234A - 7-oxabicyclo (2.2.1)heptane analogs

Info

Publication number: GB2194234A
Application number: GB08717820A
Authority: GB
Inventors: Ravi K Varma; Carl P Closek; Eric M Gordon
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1986-08-26
Filing date: 1987-07-28
Publication date: 1988-03-02
Anticipated expiration: 2007-07-28
Also published as: CA1284648C; FR2603283A1; IT8721673A0; GB2194234B; DE3728366A1; FR2603283B1; JPS6360989A; GB8717820D0; IT1222513B; US4707494A

Description

GB2194234A 1

SPECIFICATION

7-oxabicyclo(2.2.1)heptane analogs In a copending application entitled -7-OXABICYCL0(2.2.1)HEPTANE HYDROXAMIC ACID DERI- 5 VATIVES USEFUL AS 'DUAL INHIBITORS... and filed concurrently herewith, compounds capable of simultaneously inhibiting the arachidonic acid enzymes 5-lipoxygenase and cyclooxygenase are disclosed.

The present invention relates to 7-oxabicyclo(2.2.1)heptane analogs and more particularly con- cems such derivatives which are inhibitors or arachidonic acid cyclooxygenase and as such are 10 useful, for example, as antiinflammatory agents.

In accordance with the present invention new 7-oxabicyclo(2.2.1) heptane analogs useful as inhibitors of arachidonic acid cyclooxygenase are provided. These new compounds have the general formula 15 0 -(x)n -R% [I ZA 20 Z- OR2 wherein R, is lower alkyl, alkenyl, substituted alkenyl or alkynyl; R2 'S lower alkyl, alkenyl or alkyny]; A is -CH2-CH=CH- or a single bond; X is CH2, CH(CH3) or C(CH1; and n is an integer 25 from 0 to 9, with the proviso that when A is a single bond, n is an integer from 1 to 9; and including all stereoisomers thereof.

The term -lower alkyl- or---alkyl- as employed herein by itself or as part of another group includes both straight and branched chain radicals of up to 12 carbons, preferably 1 to 8 carbons, such as methyl, ethyl, propyl, isopropy], buty], t-butyi, isobutyl, pentyl, hexyi, isohexy], 30 heptyl, 4,4-dimethylpentyi, octyl, 2,2,4-trimethylpentyl, nony], decyl, undecyl, dodecyl, the vari ous branched chain isomers thereof, and the like as well as such groups including a halo substitutent, such as F, Br, Cl or 1 or CF3, an alkoxy substituent, an aryl substituent, an aralkyl substituent, a haloaryl substitutuent, a cycloalkyl substituent, an alkylcycloalkyl substituent, hy droxy, an alkylamino substituent, an alkanoylamino substituent, an arylcarbonylamino substituent, 35 a nitro substituent, a cyano substituent, a thiol substituent or an alkylthio substituent.

The term "cycloaikyi" employed herein by itself or as part of another group includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclodo decy], which groups are substituted with the same, or a different cycloalky]. 40 The term---aryl- or---Ar- as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substitutent on either the phenyl or naphthyl may be 1 or 2 lower alkyl groups, 1 or 2 halogens (Cl, Br or F), 1 or 2 lower alkoxy groups, 1 or 2 hydroxyl groups, 1 or 2 alkylamino groups, 1 or 2 alkanoylamino 45 groups, 1 or 2 arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups and/or 1 or 2 alkylthio groups.

The term---aralkyl-, "aryi-alkyi" or -aryl-lower alky]- as used herein refers to lower alkyl groups as discussed above having an aryl substituent, such as benzy].

The term -lower alkenyl- or---alkenyl- as employed herein by itself or as part of another 50 group includes an unsaturated hydrocarbon group having from 3 to 8 carbons and a single carbon-carbon double bond, such as etheny], 1-propeny], 2-propeny], 1- butenyl, 2-butenyl, 3 butenyl and the like.

The lowe r alkenyl groups can be substituted, for example, with alkyl groups, aryl groups or halogens. 55 The term "lower alkyny]- or---alkyny]as used herein by itself or as part of another group includes an unsaturated hydrocarbon group having from 3 to 8 carbon atoms and a single carbon-carbon triple bond, such as 1-propynyl, 2-propynyl, 1-butynyl, 2butyny], 3-butynyl and the like.

The term "acyl" as used herein by itself or as part of another group refers to an alkyl 60 carbonyl or alkenyl carbonyl group.

The term---aroy]- as used herein by itself or as part of another group refers to an aryl carbonyl group.

The term---halogen-or---halo-as used herein refers to chlorine, bromine, fluorine or iodine with chlorine being preferred. 65 2 GB2194234A 2 Preferred are those compounds of the invention wherein R, is methyl or 1, 1-dimethyl ethenyi, R, is hexyi, A is -CH,-CH = CH-, X is CH, and n = 1, 2 or 3.

The various compounds of the invention may be prepared as described below.

To make the compounds of formula 1 wherein A is -CH27CH=CH- and X is CH, a compound having the formula 5 0 CHZ---ca=C"-(CH2)n-COOR 7 L, CH2---O-R2 (prepared as described in United States Patent 4,582,854) can be reacted with a suspension of lithium aluminum hydride in a dry organic solvent, e.g. tetrahydrofuran at a temperature within 15 the range of from about 0' to about 2WC to afford a compound having the formula 0 M CR2--'"-HH-(CI2)n-CHZ0H 20 CR2 -0-R2 Compound Ill can thereafter be subjected to reaction with a mixture of N- bromosuccinimide and 25 triphenyl phosphine in an organic solvent, e.g. benzene or dichloromethane at about O'C to 250C to produce the compound V ----C112 --CRH-(C112)n-CH2Br 30 2 ---O-R2 35 Compound W, in a dry organic solvent, such as tetra hydrofuran, can next be reacted with lithium aluminum hydride suspended in a solvent, e.g. diethyl ether or tetra hydrofu ran, to obtain the compound of the present invention p 40 CH2 ---CH-H- (CH?.) ---CH3 17-- /- - 't '112---.0-R2 45 that is, the compounds of formula 1 wherein A is -CH,-CH=Cl-1-, X is CH2 and R, is methyl.

To make compounds of formula 1 wherein A is -CH,-CH=Cl-1-, X is CH, and P, is alkenyl, a compound of the formula 50 vi Br-CH2 ---CH2 ---CH-=C ",,"Cl13 CH3 55 is mixed with triphenylphosphine in the presence of an organic solvent, such as ocetonitrile or benzene, at a temperature within the range of from about WC to about WC to afford a compound of the formula VII CH3 60 ( C 6 H 5) 3 F_-CH2---M2 "CH3 '--tr To a suspension of compound VII in a solvent, e.g. tetrahydrofuran, at about O'C under an inert 65 3 GB2194234A 3 atmosphere, e.g. nitrogen, is added a solution potassium-t-amylate in an organic solvent such as toluene. To this is added a solution of the ether aldehyde 0 VIII C112 --- CEO /CH2---0-R2 10 in a dry solvent, e.g. tetrahydrofuran, at room temperature under an inert atmosphere to afford the compound of the invention IX CH3 15 CB2 --- CH --- CH-'CR2-"-CR' L, CH,3 C52---C-R2 20 that is, the compound of formula 1 wherein A is -CH2-CHCH-, X is CH2 and R, is alkenyi.

An alternative set of reactions for making compounds of the invention wherein R, is alkyl, alkenyl or substituted alkenyl and R2 is alkyl, alkenyl or akynyl comprise reacting a compound of the formula X 0 \ ClW' 7 CH -1^ OH 25 Ii: z: 30 with a compound of the formula Xl BR,-I(C6H5)3P(X),, R, 35 in the presence of a solvent, e.g. tetrahydrofuran and a base, e.g. potassium t-arnylate or n butyllithium to produce 0 40 XII CE2--CE==CR-(X)n-Rl E 7,. - - CH2-OR 45 Compound X11 can thereafter be reacted with X111 R2 0 Mesylate 50 in the presence of an inorganic base, e.g. potassium hydroxide and an organic solvent, e.g.

xylene, to afford compounds of the invention x,v 155 H2---CHH-(X) n" Ii 12-OR2 60 The compounds of this invention have four centers of asymmetry as indicated by the asterisks in formula 1. However, it will be apparent that each of the formulae set out about which do not include asterisks still represent all the possible stereoisomers thereof. All of the various stereoi someric forms are within the scope of the present invention.

The various stereoisomeric forms of the compounds of the invention, namely, cis-endo, cis- 65 4 GB2194234A 4 exo and all trans forms and stereoisomeric pairs may be prepared as shown in the working Examples which follow and by employing starting materials and following the procedures as outlined in United States Patent No. 4,582,854. Examples of such stereoisomers are set out below.

0 5 Ia A-(X),i-Rj H 2--OR2 H 10 (Cis-exo) Ib H 15 E E 7-K A-(X)n7 -R, C52--OR2 (cis-endo) 20 IC R A-(X)n7R, 25 2---OR2 El (trans) 30 0 Id A-(X)n-R, -H 35 H CB2 ---- OR2 (trans) 40 The nucleus in each of the compounds of the invention is depicted as 45 for matter of convenience; it will also be appreciated that the nucleus in the compounds of the invention may be depicted as 50 55 The compounds of the invention are arachidonic acid cyclooxygenase inhibitors. ThL- adminis tration of compounds of this invention to humans or animals provides a method for treating inflammation. Arthritis is preferably treated but any type of inflammatory disease where prosta- 60 glandins are involved as pharmacological mediators can be treated. In addition, compounds of the invention are analgesics and antipyretics. For example, the compounds of this invention can be used for treatment of such conditions as rheumatoid arthritis, osteoarthritis, headaches, fevers and sunburns.

An effective but essentially non-toxic quantity of the compound is employed in treatment. 65 GB2194234A 5 The compounds of the invention can be administered orally, parentally or topically to various mammalian species known to be subject to such maladies, e.g., humans, cattle, horses, cats, dogs, and the like in an effective amount within the dosage range of about 1 to 100 mg/kg, preferably about 1 to 50 mg/kg especially about 2 to 25 mg/kg on a regimen in single or 2 to 4 divided daily doses. 5 The active substance can be utilized in a composition such as tablet, capsule, solution, suspension, cream, lotion or ointment containing about 1 to about 5000 mg per unit of dosage of a compound or mixture of compounds of formula 1. They may be compounded in conven tional matter with a physiologically acceptable vehicle. or carrier, excipient, binder, preservative, stabilizer, flavor, etc. as called for by accepted pharmaceutical practice. Also as indicated in the 10 discussion above, certain members additionally serve as intermediates for other members of the group.

The following examples represent preferred embodiments of the present invention.

Example 1 15

1R-[la,2,8(Z),3,8,4a]-2-[(2-Heptenyl)]-3-[(hexyloxy)methyl]-7oxabicyclo[2.2. 1]heptane A suspension of the lithium aluminum hydride (76 mg, 1.0 mmole) in dry tetrahydrofuran (hereinafter THF) was cooled and stirred under nitrogen atmospher and a solution of 1R [la,2#(Z),3p(Z),3p,4a]-7-2]-3-[(hexyloxy)methyl]-7-oxabicyclo(2.2.1)hept2yl]-hept]-5-enoI (200 mg, 0.52 mmole) in 2.0 ml of dry THIF was added. After 5 minutes the mixture was refluxed for 2 20 hours. It was then re-cooled and decomposed by the careful addition of 10 ml of 20% hydrochloric acid. It was further diluted with brine (20 ml) and extracted three times with ether.

The extracts were combined, washed with brine and a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated to afford an oil. This was chromato graphed to afford 128 mg of 1R-[la,2p(Z),3#,4a]-2-[(2-Heptenyl)-3- [(hexyloxy)-methyl]-7-oxabicyclo[2.2.11heptane as an oil.

Example 2 fla,2,8(2Z),3,8,4a]-7-[3-[(Hexyloxy)methyll-2-(6-methyl-2,5-heptadienyl)7-o xabicyclo-[2.2. 11heptane A. (4-Methyl-3-pentenyl)triphonylphosphonium bromide 30 A mixture of 5-bromo-2-methyl-2-pentene (489.2 mg, 2 mmole) and triphenylphosphine (787 mg, 3 mmole) in 6 ml of acetonitrile was stirred at 95'C (oil bath temperature) under nitrogen for 20 hours. The solvent was evaporated by a stream of nitrogen. The residue was dried in vacuo at room temperature to give a foam. This was rinsed with ethyl ether to give a white solid which was filtered, washed with ethyl ether and dried in vacuo at 100'C for 4 hours to 35 afford 905 mg of (4-methyl-3-pentenyl)triphenylphosphonium bromide.

B. [la,2,8(2Z),3,8,4a]-7-[3-[Hexyloxy)methyl]-2-(6-methyl-2,5heptadienyl)-7-ox abicyclo-[2.2. 1Jhep tane A suspension of (4-methyl-3-pentenyl)-triphenylphosphonium bromide (850 mg, 2 mmole) in 40 ml of dry THF was chilled to OC under nitrogen. A solution of 1.68M potassium-t-amylate in toluene (0.81 ml, 1.36 mmole) was added dropwise. The resulting solution was warmed to room temperature and stirred for 30 minutes. To the so-formed solution was added a solution of [la,2fl,3fl,4a]-2-[[3-(Hexyloxy)methyll-7-oxabicyclo-(2.2.1)hept-2yl]acetai dehyde (203 mg, 0.8 mmole) in 2 ml of dry THF and stirred at room temperature under nitrogen for 2 hours. The 45 resulting solution was acidified with 5% hydrochloric acid to a pH of 2. The solution was evaporated in vacuo to remove the THF. The residue was diluted with 10 ml of water, saturated with sodium chloride and extracted four times with ethyl ether. The combined extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was chromatographed to produce 175 mg of [la,2p(2Z),3#,4a]-7-[3-[(Hexyloxy)-methyll-2-(6-methyl2,5-heptadienyl)-7-ox a- 50 bicyclo-[2.2. 1]heptane.

Examples 3 to 15 The following additional compounds within the scope of the present invention may be pre- pared by employing the teachings as outlined above and in the working examples. 55 -Wri-Rl L-St 60 CB2---OR2 (3) Ilc. No. R, R 2 A X n 3 -C3 H 7 -CH 2-CSIC-'CH3 -C112 CH 2 3 Br 4 -'CH= C --C'I3 -CH- C- C__CH3 -Cll-CH=CF, Cp^2 6 -C 4 H 9 -C 2 11 5 --CH 2 -CH=CH- C11 2 2 6 CH- CH- CH 3 -al- CH=CII- C11 2 7 - C 2 H 5 -C 3H7 0 C) Ex. No. R 1 R 2 A X n 8 -c 2 H 5 -c 3 1 cl! (C11 3) 2 / C11 3 9 -CH=C -c F - CH - (II -- CH- CH 4 2 'S 2 2 CH 3 -CH 2 - C':mc - CH CH - CII-CEI-C 1,r cl CH C (C113) 2 3 2 2 3 12 - Cl' = -CH 3 -c 2 115 _al 2- CH-CH-- CH 2 5 cl 1 -CP15 -- Cl] 2- CH=Cli- aj-2 2 12 -CH"-ui-ui-aI 3 CD r11) m -Pb N W P.

i Ex. No. R 1 R 2 A X 13 -01 2-CH=CH_% -c 3 1 (C(Cl 3)2 2 14 -C 3 H 7 -c 3H7 -GI 27 CH=CH- CH 2 3 is -CH=CH-CH 3 CH 2-CH=C"'-CII 3 -CH 2 -Qi=Cll-CH 2 4 G) 4- 00 9 GB2194234A 9

Claims

1. A compound of the formula E:tT-(X)n7R1 5 CH2 --OR2 wherein R, is lower alkyl, alkenyl, substituted alkenyl or alkynyl; R2 is lower alkyl, alkenyl or 10 alkynyl; A is -CH2-CH=CH- or a single bond; X is -CH, -CH(CH3) or C(CH3)2; n is an integer from 0 to 9; including all stereoisomers thereof.

2. A compound of claim 1 wherein R, is alkyl, R, is alkyl, A is -CH,CH=CH-, X is -CH2 and n=

3. 15 3. A compound of claim 1 wherein R, is alkenyl, R, is alkyl, A is -CH2- CH=CH-, X is -CH2 n= 1.

4. A compound of claim 1 having the name 1R-[la,2fl(5Z),3p,4a]1-2-(2Heptenyl)-3-[(hexyloxy- methyl]-7-oxabicyclo[2.2. 1]heptane.

5. A compound of claim 1 having the name la,2,6(2Z),3fl,4a]-7-[3[(hexyloxy)methyl]-2-(6- 20 methyl-2,5-heptadienyl)-7-oxabicyclo-[2.2. 1]heptane.

6. A composition for treating inflammation in a mammalian species comprising administration of an effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

7. A method of inhibiting arachidonic acid cyclooxygenase in mammalian species which com- 25 prises administering to the circulatory system of host an effective amount of a compound as defined in claim 1.

8. The method of claim 11 wherein said compound is administered in an amount within the range of from about 1 to about 100 mg/kg.

9. A method for treating fever, pain, and inflammation in a mammalian species in need of 30 such treatment, which comprises administering to host an effective amount of a compound as defined in claim 1.

10. A method of treating sunburn in a mammalian species in need Of such treatment which comprises administering to host topically an effective amount of a compound as defined in claim 1 in a pharmaceutically acceptable carrier. 35 Published 1988 at The Patent Office, State House, 66/71 High Holborn, London WC 1 R 4TP. Further copies may be obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Burgess & Son (Abingdon) Ltd. Con. 1/87.